Pharmaceutical levothyroxine preparation

ABSTRACT

The invention relates to a pharmaceutical preparation comprising levothyroxine sodium, potassium iodide, microcrystalline cellulose and binding agent, which is free of antioxidants or further auxiliaries, and processes for its production.

This application is a 371 of PCT/EP99/04485 filed Jun. 29, 1999.

The invention relates to a novel stable pharmaceutical preparationcomprising levothyroxine sodium, potassium iodide, microcrystallinecellulose and binding agent, which is free of antioxidants or furtherauxiliaries.

Auxiliaries are substances which prevent formation of iodine, e.g.potassium hydroxide.

A thyroxine preparation stabilized with thiosulfate as an antioxidant isdescribed in DE 195 41 128.

Another known thyroxine-containing commercial preparation Thyreocomb® N(Red List 1998, 74015) contains the auxiliary potassium hydroxide, whichdrives the comproportionation reaction of iodide and iodate to iodine tothe starting material side. In this manner, production of iodine issuppressed.

A preparation comprising levothyroxine sodium and potassium iodide forthe stabilization of the active compound levothyroxine sodium isdisclosed in U.S. Pat. No. 5,635,209. For a low dose, the amount ofpotassium iodide needed for the stabilization of levothyroxine sodium isgiven in a ratio of 4:1, e.g. 25 μg of levothyroxine sodium and 100 μgof potassium iodide. For high doses, the ratio is described as 1.5:1,e.g. 300-450 μg of potassium iodide for 300 μg of levothyroxine sodium.300 μg of potassium iodide were needed for the stabilization of 100 μgof levothyroxine sodium.

The active compound levothyroxine sodium (=levothyroxine-Na=LT4) issensitive to light, heat and oxygen. On account of these known stabilityproblems, pharmaceutical preparations are therefore overdosed by up to20%.

If, in addition to the active compound levothyroxine-Na in apharmaceutical preparation, iodide is additionally contained, thispharmaceutical preparation becomes discoloured on storage, since theanion iodide in potassium iodide can be oxidized to iodine or cancomproportionate with potassium iodate to give iodine. Furthermore, thedemands on the in-vitro release for levothyroxine-Na tablets have beenincreased. The draft monograph of the Pharmacopeial Forum (Pharm.Preview, 1995, 21, 1459-1461) intends, in addition to the valid test 1(phosphate buffer pH 7.4, in 80 minutes >55%), to approve the test 2(water in 45 minutes >70%).

The invention was based on the object of making available novelmedicaments in the form of pharmaceutical preparations which have betterproperties than known medicaments which can be used for the samepurposes.

This object was achieved by the discovery of the novel preparation.

The novel preparation according to the invention essentially shows nodiscolouration and has an improved stability. It can be used as athyroid hormone combination preparation, owing to the high content ofiodide as a second active compound, in euthyroid iodine deficiencygoitre and/or in relapse prophylaxis after resection of an iodinedeficiency goitre.

The active compound iodide can be contained as an anion only in thepresence of a stabilizing cation, e.g. potassium (⁺), and thus as a saltin a pharmaceutical preparation. 130 μg of potassium iodide correspondto 100 μg of iodide.

Discolouration of the preparation according to the invention is avoided,since formation of free iodine is prevented.

This novel preparation furthermore has a very good release of activecompound in vitro.

The invention preferably relates to a pharmaceutical preparation asdescribed, characterized in that it contain 5 to 400 μg, oflevothyroxine 300 μg, in particular 50 to 200 μg, of levothyroxinesodium and 5 to 400 μg, preferably 10 to 300 μg, in particular 25 to 200μg, of potassium iodide.

The invention furthermore preferably relates to a pharmaceuticalpreparation as described, characterized in that it containslevothyroxine sodium in micronized form having a particle size ofbetween 5 and 25 μm (to 95%), particularly preferably having a particlesize of between 5 and 15 μm (to 95%).

The invention furthermore preferably relates to a pharmaceuticalpreparation as described, characterized in that it contains ahydroxypropyl-methylcellulose and/or gelatine as a binding agent.

A pharmaceutical preparation is particularly preferably described,characterized in that it is a solid preparation in the form of tablets.

Particularly preferred embodiments contain 50, 75 or 100 μg oflevothyroxine sodium and 100 μg each of iodide, 100 μg of iodidecorresponding to an amount of 130 μg of potassium iodide. A veryparticularly preferred embodiment contains 100 μg of levothyroxinesodium and 100 μg of iodide.

On account of the known instability of levothyroxine-Na, this activecompound is overdosed to 5% in the formulations.

The preparation according to the invention has a surprising stabilitywhen hydroxypropylmethyl-cellulose and/or gelatine is used as a bindingagent. At the same time, formation of iodine is surprisingly suppressedwithout admixture of antioxidants or further auxiliaries beingnecessary.

The data of the stability investigations are indicated in Tables I andII as exemplified by batches 005204 (13/97) and 004609 (3/96). Based onthe results, it can be seen that the tablets according to the inventionwhich contain levothyroxine sodium (100 μg) and iodide (100 μg) arestable for at least 2 years if they are stored at temperatures below 30°C. Likewise, no brown colouration of the pharmaceutical preparation isobserved in this period, i.e. no formation of iodine.

Furthermore, the release of the active compound levothyroxine sodium isfavoured if the active compound is employed in micronized form.Levothyroxine sodium is customarily soluble with great difficulty bothin water and in ethanol. With a particle size of between 5 and 25 μm (to95%), particularly preferably between 5 and 15 μm, however, a release ofthe active compound which corresponds to both test systems takes place(Tables I and II).

TABLE I Stability and release of batch 005204 (13/97); levothyroxine-Na(LT4) 100 μg/iodide 100 μg tablets; prepared analogously to Example 1:PP tube 25°/60% Release Release Water content Period Content Contentwith with according Disintegration Date (storage) of LT4 of iodidebuffer water to KF time Friability Date (investigation) [μg] [μg] [%][%] [%] [sec] [N] Starting value 108.3 99.5 30 min: 94.3 15 min: 91.32.51 43-55 42-50 60 min: 99.2 30 min: 93.5 80 min. 100.6 45 min: 95.1 13weeks 106.9 104.2 15 min: 85.9 3.28 50-60 48-55 18.07.1997 30 min: 89.913.02.1998 45 min: 91.2 26 weeks 102.1 102.8 15 min: 89.5 3.14 50-6841-48 17.10.1997 30 min: 91.6 21.02.1998 45 min: 95.1 39 weeks 100.6103.2 15 min: 84.6 3.28 49-60 41-49 19.01.1998 30 min: 88.1 45 min: 89.352 weeks 100.9 103.2 15 min: 84.6 3.50 40-55 41-49 30 min: 87.2 45 min:89.5 Comments: 5% overdosage of LT4

TABLE II Stability and release of batch 004609 (3/96); levothyroxine-Na(LT4) 100 μg/iodide 100 μg tablets; prepared analogously to Example 1:PP blister 25°/60% Release Release Water content Period Content Contentwith with according Disintegration Date (storage) of LT4 of iodidebuffer water to KF time Friability Date (investigation) [μg] [μg] [%][%] [%] [sec] [N] Starting value 108.3 103.6 30 min: 105.3 15 min: 101.03.18 60 min: 105.3 30 min: 102.9 80 min: 103.1 45 min: 106.1 13 weeks104.9 100.2 15 min: 94.6 4.8 23.12.1996 30 min: 96.3 45 min: 96.7 26weeks 104.8 103.6 15 min: 96.1 5.34 10.04.1997 30 min: 97.2 24.02.199845 min: 97.4 52 weeks 101.5 102.7 15 min: 94.1 6.26 37-50 39-4429.09.1997 30 min: 95.3 45 min: 95.8 78 weeks 99.72 104.6 15 min: 95.85.69 30-38 35-40 24.02.1998 30 min: 97.5 45 min: 98.6 Comments: 5%overdosage of LT4

The analytical data are determined according to customary and knownmethods.

The invention also relates to a process for the production of apharmaceutical preparation comprising levothyroxine sodium and potassiumiodide, characterized in that levothyroxine sodium and potassium iodide,which are present in suspended form in aqueoushydroxypropylmethylcellulose and/or gelatine solution, are sprayed ontothe microcrystalline cellulose in a fluidized bed granulation, then adisintegrating agent and lubricant are admixed and the mixture iscompressed to give tablets.

Hydroxypropylmethylcellulose and potassium iodide are dissolved in waterand levothyroxine sodium is suspended in water at temperatures between 5and 40° C., preferably between 10 and 35° C., particularly preferablybetween 15 and 30° C.

The temperature during the granulation is between 60 and 80° C.,preferably between 65 and 75° C., at the inlet and between 10 and 50°C., preferably between 20 and 40° C., at the outlet. The spray pressurein the process according to the invention is between 3 and 5 bar.

The invention further relates to a process as described, characterizedin that the disintegrating agent used is croscarmellose sodium and thelubricant used is magnesium stearate.

Further excipients or additives can be added, such as, for example,binding agents, colourants, lubricants, sweeteners and/or aromaticsubstances.

Preferred glidants or lubricants are, for example, talc, starch,magnesium stearate and calcium stearate, boric acid, paraffin, cocoabutter, macrogol, leucine or sodium benzoate; magnesium stearate is veryparticularly preferred.

The preparation according to the invention can be prepared without theuse of organic solvents.

The following examples relate to the production and the composition ofthe pharmaceutical preparation according to the invention:

EXAMPLE 1

The following amounts are needed in order to prepare, for example,50,000 tablets:

Levothyroxine 100 μg/iodide 100 μg Ingredient Amount [g] Levothyroxinesodium* 5.25 Potassium iodide 6.54 Hydroxypropylmethylcellulose 175.00Microcrystalline cellulose 4125.70 Croscarmellose sodium 175.00Magnesium stearate 12.50 Water, purified** 3259.00 *A 5% overdosage forlevothyroxine sodium was additionally included. **The water is removedagain by drying.

Production

1. Hydroxypropylmethylcellulose and potassium iodide are dissolved inabout 90% of the water at room temperature with stirring.

Levothyroxine sodium is suspended in about 10% of the water at roomtemperature.

The suspension is then combined with thehydroxypropylmethylcellulose/potassium iodide solution with the aid of amixer.

2. The microcrystalline cellulose is introduced into a fluidized bedgranulator. The granulating liquid is sprayed over the powder. Duringthe granulation, the temperature is kept at approximately 7° C. (+5° C.)at the inlet and between 20 and 40° C. at the outlet. The spray pressureis between 3 and 5 bar.

After spraying, the granules are dried until a temperature ofapproximately 40° C. is reached at the outlet.

The dry granules are then sieved (1 mm) according to known methods(=mixture a).

Croscarmellose sodium and magnesium stearate are correspondingly sieved.The components are then mixed with one another for 10 minutes in a drummixer together with mixture a.

The ready-to-press mixture is then compressed to give tablets.

EXAMPLE 2

Composition of a 90 mg (±3 mg) tablet which contains 105 μg oflevothyroxine sodium and 130 μg of potassium iodide and thus 100 μg ofiodide:

levothyroxine sodium 0.105 mg potassium iodide 0.1308 mg water* 65.00 mghydroxypropylmethylcellulose 3.50 mg cellulose, microcrystalline 82.514mg croscarmellose sodium 3.50 mg magnesium stearate 0.25 mg 90.00 mgLevothyroxine sodium is overdosed by 5%. *water is removed by drying.

Comparison Example

The following amounts are needed in order to prepare, for example,60,000 tablets:

Levothyroxine 100 μg/KI 300 μg Ingredient Amount [g] Levothyroxinesodium* 7.03 Potassium iodide 17.99 Cellulose 5885.72 Croscarmellosesodium 50.00 Magnesium stearate 25.00 Water, purified** 4140.00 *A 5%overdosage for levothyroxine sodium was included. **The water is removedagain by drying.

Preparation

1. Levothyroxine sodium (1.05%) and about 10% of the cellulose aresieved and mixed for 20 minutes in a Turbula mixer.

2. The potassium iodide (18%) is dissolved in 60% of the water. 54% ofthe cellulose is moistened with this solution and the treated celluloseis kneaded and sieved (1 mm). After drying in vacuo at room temperature,the resulting granules (0.1% of KI) are sieved through a 0.75 mm sieve.

3. The remaining amount of potassium iodide (82%) is applied tocellulose in the third stage analogously to stage 2. Sieved granulescomprising 0.7% of KI are obtained.

4. Sodium carboxymethylcellulose (Croscarmellose sodium) and magnesiumstearate are correspondingly sieved (0.5 mm).

5. The granules or solid mixtures obtained from stages 1 to 4 arecombined and mixed according to known methods for 20 minutes. Tablettingis carried out in a rotary press (13 kN press force).

The tablets are yellow- to brown-coloured.

What is claimed is:
 1. A pharmaceutical composition comprisinglevothyroxine sodium, potassium iodide, microcrystalline cellulose andhydroxypropylmethylcellulose or gelatine or bothhydroxypropylmethylcellulose and gelatine, which is essentially free ofantioxidants.
 2. A pharmaceutical composition according to claim 1comprising 5 to 400 μg of levothyroxine sodium and 5 to 400 μg ofpotassium iodide.
 3. A pharmaceutical composition according to claim 1wherein the levothyroxine sodium is in micronized form having a particlesize of 5 to 25 μm.
 4. A pharmaceutical composition according to claim1, wherein the composition is solid in the form of tablets.
 5. A processfor the preparation of a pharmaceutical composition comprisinglevothyroxine sodium, potassium iodide, microcrystalline cellulose and abinding agent, which is essentially free of antioxidants, said processcomprising spraying an aqueous hydroxypropylmethylcellulose and/orgelatine solution comprising levothyroxine sodium and potassium iodidewhich are present in suspended form in said solution ontomicrocrystalline cellulose in a fluidized bed granulation, admixing adisintegrating agent and a lubricant and compressing the resultantmixture to form tablets.
 6. A process according to claim 5, wherein thedisintegrating agent is croscarmellose sodium and the lubricant ismagnesium stearate.